Leprosy, a human disease caused by the intracellular pathogen Mycobacterium leprae (mLEP), offers an attractive model for investigating the regulation of innate and adaptive immune responses to infection in skin. The disease represents a spectrum, in which the clinical manifestations correlate with the immune response to the pathogen. By investigating the adaptive immune response in leprosy, we established that resistant, self-limited, tuberculoid (T-lep) patients express the Thi cytokine IFN-gamma in lesions, whereas disseminated lepromatous (L-lep) patients manifest Th2 cytokines IL-4 and IL-10 in lesions (1). Our new preliminary data indicates the differential expression of interferons (IFNs) and their downstream gene networks in leprosy skin esions. The striking finding was that expression ofthe Type II IFN, IFN-gamma, as well as IFN-gamma inducible genes including the antimicrobial gene program, were enriched in T-lep lesions. In contrast, expression ofthe Type IFN, IFN-Beta, as well as IFN-Beta inducible genes, predominated in L-lep lesions. We hypothesize that specific mLEP secreted proteins/ligands differentially trigger production of Type II vs. Type I IFNs in T-lep vs. L-lep patients, respectively. To test this hypothesis, we propose translational experiments to: 1) identify the T cell epitopes/antigens in the putative mLEP secretome which induce the Type II IFN, IFN-gamma, in leprosy patients and trigger an antimicrobial activity, 2) determine whether specific mLEP secreted proteins induce Type I IFNs and inhibit antimicrobial responses; and, 3) investigate the mechanism by which the secreted mLEP glycolipid, phenolic glycolipid-1 (PGL-1), triggers Type I IFN responses in monocytes/macrophages. The studies we propose are intended to provide a comprehensive analysis of the mechanisms that trigger Type I vs. Type II IFNs in leprosy, including the role of these pathways in host defense and pathogenesis. We would hope that insights would assist in the diagnosis and prevention of leprosy, as well as provide new avenues for development of immunomodulatory approaches for a variety of human skin diseases.